PTP1B inhibitors: Synthesis and evaluation of difluoro-methylenephosphonate bioisosteres on a sulfonamide scaffold

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 8; pp. 2719 - 2724
• Main Authors: Holmes, Christopher P., Li, Xianfeng, Pan, Yijun, Xu, Caiding, Bhandari, Ashok, Moody, Claire M., Miguel, Joy A., Ferla, Steven W., De Francisco, M. Nuria, Frederick, Brian T., Zhou, Siqun, Macher, Natalie, Jang, Larry, Irvine, Jennifer D., Grove, J. Russell
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.04.2008; Elsevier
• Subjects: Bioisostere; Biological and medical sciences; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Fluorine Compounds - chemical synthesis; Fluorine Compounds - chemistry; Fluorine Compounds - pharmacology; General and cellular metabolism. Vitamins; Medical sciences; Molecular Structure; Organophosphorus Compounds - chemical synthesis; Organophosphorus Compounds - chemistry; Organophosphorus Compounds - pharmacology; Pharmacology. Drug treatments; Phosphatase; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; PTP1B; Structure-Activity Relationship; Sulfonamide; Sulfonamides - chemistry; PTP1B; Sulfonamide; Bioisostere; Phosphatase; Enzyme; Phosphoric monoester hydrolases; Enzyme inhibitor; Esterases; Acetic acid derivative; In vitro; Structure activity relation; Hydrolases; Benzenic compound; Bromine Organic compounds; Fluorine Organic compounds; Chemical synthesis; Protein-tyrosine-phosphatase
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.03.007

We have synthesized and evaluated a series of triaryl sulfonamide-based PTP1B inhibitors in which a difluoro-methylenephosphonate group of a potent lead has been replaced by potential bioisosteric replacements. Several mono- or di-charged compounds ( 8a, 8b, and 15a) were shown exhibit inhibitory activity in the low micromolar range, demonstrating the feasibility of using this approach in identifying non-phosphonate pTyr mimetics in a small molecular scaffold. These results also provide a useful indication of the relative effectiveness of these pTyr mimetics.